Saturated dithienyl propyl amines and process of making



Patented Aug. 17, 1954 r I e r i f -2,688,785 sa'roaa'ran DITHIENYL PROPYL AMmEs AND raocnss or MAKING Walter Mark Damn, Iiondon, England, assignor to Burroughslwellcome &Co."(U. S. A.) Inc.,

r a Tuckahoa'No Y; a corporation of New York No Drawing. Application April 24, 1951,

Serial No. 222,751

. claims priority,

The present invention relates to chemical com pyrrolidino or piperidino-groups, are already.

known, various members of the series being described for examplein co-pending U. S. application Serial No. 104,810, filed July 14, 1949, now

' U. s. Patent No. 2,561,899. They may be formed by dehydration of the corresponding carbinols, which themselves may be formedby a variety of .synthetic routes. 1 y r Attempts to reduce thecompounds of the type (1) why many usual hydrogenating. processes ,eitheru fail altogetheror result in attack of, the -thienylgroups. We have now foundwthatthe double bond can be reducedby means of metal lic sodium without at the same time attacking the thienyl groups whereby compounds of the general formula r i j j Th2CH.CI-I2.CHR .NR R (II) where Th, R R. and R or NRR have the same meanings given above, are produced. Such compounds arenovel and some are found to have a valuable analgesic and some a spasmolytic activity. Analgesic activity is most prominent in those compounds wherein R =CH3. pounds are conveniently administered in the form oitheir salts such as their hydrochlorides.

The identity of the acid used for preparing the salt is ofno consequence for the physiological activity, however, providing it is not itself highernecl by availability or convenience and all salts of the compounds of this invention with nontoxic acids are considered equivalent. For purposes of this applicatiomthe base and non-toxic "the advantage in presentation, comparedwith analogous known dithienyl alkenylamines, that "they are more stableto heat and to exposure t air which facilitates their sterilization. r

The com- The present invention therefore comprises a process for the production or; compounds of the application Great Britain April za iaso 4 r 11 Claims. (crest-293.4)

fined to reduction under such conditions that the thienyl groups are not attacked while. the double bond is reduced, for example by means of metallic sodium in an alcohol (preferably an alcohol having not more than 6 carbon atoms) with or without theaddition of water or in liquidam- '"monia, or by sodium amalgam and acid: While these variations are equivalent in that they all suflice to produce the desired. reduction, they are not all equally-convenient or eificient. The reductionsineth'anol frequently are incomplete and yields are in all cases less than quantitative, usually in the range 'of -70%. When complete reduction is secured the loss (from the quantitativeyielm is due to de-am'ination which proceeds concurrently. Such cleavages are relatively' prominent when amyl alcohol is used as the solventforwhich reason, and also because it is harder to get rid of amyl alcohol" at the end of the reduction, it is preferred to use propanol (either nor iso), or 80% ethanol. Completeness ofreduction can be determined by the absorption spectrum of the product. The parent allylamines possess intense absorption (t=14,l00)' at 290m whereas the saturated amines have only feeble" absorption (e -8 00) at that wave length.

Alternatively, if a sample containing some of the unsaturated amine is heated to boiling in concentratedhydrochloric acid an orange color develops, which, on standing 15-30 minutes becomes an intense blue. This test, which is very sensitive has proved of great utility in determining the conditions for securing complete reaction in these reductions. The invention also provides new pharmaceutically active compounds, having analgesic and spasmolytic properties, of the general formula (II) above defined. Particularly the invention comprises the compounds herein described or ,salts thereof. r

The invention is illustrated by the following examples:

Example 1 Sodium metal (7 g.) was added graduallyto a boiling solution of 3-dimethylamino-1zl-di- 2-thienylbut-1-ene (5 g.) in ethanol (ml). When all had dissolved, the alcohol was evaporated, and the residue dissolved in water and ex tracted with ether, yielding S-dimethylamino- 1:1-di,-2'-thienylbutane (3 g.), the hydrochloride of which had a melting point 16l-162 C.

U r r r Example 2 WA boi n so utio 01 Y i il-d -z? 3 thienybut-l-ene g.) in ethanol (70 ml.) was added to sodium metal ('7 g.) and worked up as above, yielding 3 -pyrrolidino 1 1-.-di-2-thienylbutane (3 g.)'; 1-the hydrochloride of which melted at 154 C.

Example 3 Sodium metal (7 g.) was-added toa'boiling-Q solution of 3 dimethylamino-l:1-di-2'-thienylbut-l-ene (5 g.) in amyl alcohol (100 ml) and, worked up as above, yielding 3- dimethylaminol:l-di-2-thienylbutane (2.7g).

Example 4 l To a solution of 3-dimethylamino-l:I di-Z' ylbut-l-ene (5 g.) in 2 N-hydrochloric acid g was added 3% sodium amalgam (250 g.). the reaction was complete, the aqueous layer was decanted, treated with excess ammonia solution of specific gravity 0.880 and extracted with ether,

to :yield 3-dimethylamino 1:1 di-2-thienylbutane (1.5 g.

Example ,5

A slight excess of sodium metal was added to 3-dimethylamino 1:1 di 2' thienylbut-l-ene (5 g.) in a mixture of equal parts of ether. and liquid ammonia. After the addition of excess ammonium chloride, the ammonia was allowed to evaporate and from the ether was obtained 3-dimethylamino-l :1 -di-2'-thienylbutane (1.4 g.)

Example 6 Seven g. of sodium metal was added to a boiling solution of 5 g. of 3-dimethylamino-l,ldi-2- thienylbutane in 100 cc. of n.-propanol. When all the sodium had dissolved, the ropanol was evaporated and the residue was dissolved in water and extracted with ether yielding 3.5 g. of 3-dimethylamino 1,-di-2-thienylbutane, identical with that obtained in Example 1. 1

Example 7 chloride, melting at,185-186 C.)

3-dimethylamino-l 1 di-QT-thienylprop-leene gave 3-dimethylamino-1 1-di-2' thienylpropane (oxalate, melting at 182-183 'C'.)

3-dimethylamino-1:1-di-2"-thienylhex 1 -,ene gave 3-climethylamino-1: 1'-di-2' -thienylhexane (hydrochloride, melting at 136 C.).

3-ethylmethylamino 1:1 di-2-thienylbut-1- ene gave 3 -ethylmethy1amino-1: 1-di-2-thienylbutane (hydrochloride melting at 124-125 C.).

L claimi. 1, Compounds of the class consisting of those having the formula where. N=B is a member of the grou consisting of dimethylamino, diethylamino, methylethyl amino, piperidino and pyrrolidino, and their nontoxic acid addition salts.

2. As a :new compound 3 diethylamino-lzl-di- 2 -thienylbutane.

3. As a new compound 3 -pyrrolidino l 1-di-2'- i ythienylbutane.

4. As a new compound 3-piperidino-1:1-di-2'- 'thiel'iylbutane;

5." Asa new compound 3-dimethylamino-1zldi-iZFthienylbutane, v

a a new compound S-methylethylamino- 1: 1--di-2 -thienylbutane.

7. lhe process of producing bases of the forwhere-R "is a member selected from the group consisting of lower alkyl groups and hydrogen,

N=B is a member of the; group lower dialkylamino, :piperidino, .pyrrolidino a and morpholino. which consists of reducing the corresponding unsaturated. amine (new while dissolved in solvent and metalreducing combinations selected from the. class consisting of (a) sodium metal and a lower alcohol (b) sodium metal and liquid ammonia and (6) sodium amalgam and a dilute aqueous mineral acid.

8. The process of producing bases of the formula S V CHOH2(EHN=B 2 R where R, is a member selected from the group consisting of lowerfalkyl groups and hydrogen,

N=B is a member of the group lower dialkylamino, piperidino, pyrrolidino and morpholino, which consists of reducing the corresponding unsaturated amine 1 with metallic sodium while dissolved in n-propanol. a I .9. The process of producing bases of the formula where R is a member selected from the group consisting of lower alkyl groups and hydrogen, llr-B is a member of the group .0Wer dialkyl- -amino,.piperidino, pyrrolidino and morpholino,

which consists or reducing the corres onding 11 isaturated amine with metallic sodium-while dissolved in isopro- 'panol. J

10. The process of producing hasesof the-forwhere R is a member selected from the group consisting of lower alkyl groups and hydrogen, N 3 is a member of the group lower dialkylamino, piperidino, pyrrolidino and morpholino, which consists of reducing the corresponding unsaturated amine with metallic sodium while dissolved in n-butanol.

11. The process of producing bases of the formula I CHOHziH-N=B where R is a member selected from the group consisting of lower alkyl groups and hydrogen, N=B is a member of the group lower dialkylamino, piperidino, pyrrolidino and morpholino, which consists of reducing the corresponding unsaturated amine 6 with metallic sodium while dissolved in 80% aqueous ethanol.

References Cited in the file of this patent UNITED STATES PATENTS Number Name Date 2,446,522 Bockmuehl et a1. Aug. 10, 1948 2,556,636 Sperber et al June 12, 1951 2,561,899 Adamson July 24, 1951 Sperber et a1. July 22, 1952 1 OTHER REFERENCES 

1. COMPOUNDS OF THE CLASS CONSISTING OF THOSE HAVING THE FORMULA 